Robinow Syndrome is the most well-known of a group of genetic conditions that affect how bones grow and develop. Patients with these diseases exhibit short limb dwarfism at the age of 18 months and face deformities such as cleft palate.

Robinow Syndrome is a group of genetic conditions that impact bone growth and development. Individuals with these disorders typically manifest short limb dwarfism by the age of 18 months and experience facial malformations like cleft palate.

Researchers from Nationwide Children’s Hospital in Ohio and the Van Andel Research Institute in Michigan have now demonstrated the first successful limb length correction in a mouse model of a condition known as FZD2-associated autosomal dominant Robinow Syndrome, raising the possibility of new treatments.

Although autosomal dominant Robinow Syndrome illnesses are relatively uncommon (affecting only 50 families globally), they are connected with genetic differences (mutations) in a collection of genes that may be inherited from one parent or occur spontaneously, making diagnosis difficult. 

“We began the project by studying the genomes of families with structural birth differences of the brain and face who had not yet received a genetic diagnosis,” says lead author Prof. Rolf Stottmann, adding, “we identified that one of the initial families in this cohort had a mutation in the FZD2 gene.”

Today, it is understood that FZD2 is one of the genes connected to autosomal dominant Robinow Syndrome. FZD2 produces a protein that functions in delivering signals that cells use to organize themselves into tissues, much like the other genes in this family.

In their research, Professor Stottmann and colleagues employed CRISPR/Cas9 genome-editing technology to create mutations in a particular area of Fzd2, replicating the kinds of mutations seen in patients with human disease.

Mice with these mutations showed facial and skeletal deformities like the patients, including cleft palates and limbs half the size.

The researchers hypothesized that the Fzd2 mutations they were looking at would interfere with signaling and slow down bone development. Scientists gave pregnant mice a drug that speeds up the signaling pathway so that the missing signals could be sent again. 

“This drug is an attractive option,” explains prof. Stottmann, “because we think we know how it works and previous work had shown that it could rescue cleft palates in a mouse model.”

They were surprised to find that the pups who were given the drug had much longer limbs than the model mice who were not given the drug.

The fact that these experiments worked on mice suggests that the drug could also be used to treat people. 

“The idea of treating the limb bones medically rather than surgically,” according to the author, “is a really important proof of principle, which we demonstrate in this study.” 

“We are very excited to test if this could work in the context of other genes associated with autosomal dominant Robinow Syndrome.”

Source: 10.1242/dev.201038

Image Credit: Sanika Vaidya